scholarly journals CHEK2∗1100delC Mutation and Risk of Prostate Cancer

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Victoria Hale ◽  
Maren Weischer ◽  
Jong Y. Park
Keyword(s):  
Prostate Cancer ◽  
Current Knowledge ◽  
Prostate Cancer Screening ◽  
Critical Role ◽  
Prostate Cancer Risk ◽  
Conclusive Evidence ◽  
Increased Risk ◽  
History Of ◽  
Cancer Studies

Although the causes of prostate cancer are largely unknown, previous studies support the role of genetic factors in the development of prostate cancer.CHEK2plays a critical role in DNA replication by responding to double-stranded breaks. In this review, we provide an overview of the current knowledge of the role of a genetic variant, 1100delC, ofCHEK2on prostate cancer risk and discuss the implication for potential translation of this knowledge into clinical practice. Currently, twelve articles that discussedCHEK2∗1100delC and its association with prostate cancer were identified. Of the twelve prostate cancer studies, five studies had independent data to draw conclusive evidence from. The pooled results of OR and 95% CI were 1.98 (1.23–3.18) for unselected cases and 3.39 (1.78–6.47) for familial cases, indicating thatCHEK2∗1100delC mutation is associated with increased risk of prostate cancer. Screening for CHEK2∗1100delC should be considered in men with a familial history of prostate cancer.

Profile study: Genetic prostate cancer risk stratification for targeted screening.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5054-5054
Author(s):  
Elena Castro ◽  
Elizabeth Bancroft ◽  
Natalie Taylor ◽  
Tokhir Dadaev ◽  
Elizabeth Page ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Model ◽  
Genetic Risk Score ◽  
Prostate Cancer Risk ◽  
Screening Tools ◽  
Risk Scores ◽  
Severe Side Effect ◽  
Cancer Worry ◽  
Increased Risk

5054 Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA<3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.

Germline heterozygous BLM mutations and prostate cancer risk.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 321-321
Author(s):  
Elisa Ledet ◽  
Emmanuel S. Antonarakis ◽  
Colin Pritchard ◽  
William B. Isaacs ◽  
A. Oliver Sartor
Keyword(s):  
Prostate Cancer ◽  
Cancer Risk ◽  
Dna Sequencing ◽  
Cancer Patients ◽  
Genetic Disorder ◽  
Prostate Cancer Risk ◽  
Dna Helicase ◽  
Cancer Center ◽  
Increased Risk

321 Background: The BLM gene encodes a RecQ DNA helicase that is involved in homologous recombination. Biallelic BLM inactivation leads to Bloom syndrome, an inherited genetic disorder marked by chromosomal instability and multiple cancer susceptibilities. Conflicting studies have suggested that heterozygous BLM mutation carriers may have an increased risk of various cancers. Here we explored the role of germline pathogenic BLM mutations in prostate cancer. Methods: Prostate cancer patients with heterozygous BLM mutations were assembled from Tulane Cancer Center (TCC), Johns Hopkins Hospital (JHH) and University of Washington (UW). BLM germline mutations were identified either through commercial germline testing (Invitae), the UW-BROCA panel, or whole-exome sequencing. Corresponding tumor tissue was analyzed by DNA sequencing for somatic alterations. Population level control data were obtained from the Genome Aggregation Database (gnomAD). Results: 6 BLM germline carriers were identified among 985 advanced prostate cancer case; 2/295 TCC patients, 2/172 JHH patients, and 2/518 UW patients. Overall, pathogenic BLM mutations were detected in 0.609% (6/985) of prostate cancer cases. All mutations were loss-of-function truncating lesions (splicing or nonsense alterations). No Ashkenazi BLM mutations were observed. The population frequency of pathogenic or likely pathogenic BLM alterations detected in gnomAD was 0.025% (31/124,589). Compared to gnomAD controls, the relative risk of BLM mutations in prostate cancer patients was 24.3 (95% CI 10.2 to 58.2; P < 0.0001). One family had a pathogenic splice variant in BLM that cosegregated with disease in three of three cases with lethal/high risk prostate cancer. Tumor DNA sequencing was possible in 5 of 6 BLM carriers; no case demonstrated LOH or additional somatic BLM mutations. Interestingly, 2/5 cases on tumor sequencing also had bi-allelic BRCA2 inactivation. Conclusions: Germline BLM mutations may play a role in prostate cancer risk. Given the role of BLM in chromosomal stability and evidence of concurrent BRCA2 inactivation in a subset of cases, larger cohorts and functional analyses will be critical for better understanding the role of BLM in prostate cancer.

scholarly journals Polymorphisms in Genes Encoding Glutathione Transferase Pi and Glutathione Transferase Omega Influence Prostate Cancer Risk and Prognosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Veljko Santric ◽  
Dejan Dragicevic ◽  
Marija Matic ◽  
Milica Djokic ◽  
Marija Pljesa-Ercegovac ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Glutathione Transferase ◽  
Redox Homeostasis ◽  
Prostate Cancer Risk ◽  
Gst Polymorphisms ◽  
Increased Risk ◽  
Genes Encoding ◽  
Gst Polymorphism ◽  
First Time

Considering the pleiotropic roles of glutathione transferase (GST) omega class members in redox homeostasis, we hypothesized that polymorphisms in GSTO1 and GSTO2 might contribute to prostate cancer (PC) development and progression. Therefore, we performed a comprehensive analysis of GSTO1 and GSTO2 SNPs’ role in susceptibility to PC, as well as whether they might serve as prognostic biomarkers independently or in conjunction with other common GST polymorphisms (GSTM1, GSTT1, and GSTP1). Genotyping was performed in 237 PC cases and 236 age-matched controls by multiplex PCR for deletion of GST polymorphisms and quantitative PCR for SNPs. The results of this study, for the first time, demonstrated that homozygous carriers of both GSTO1*A/A and GSTO2*G/G variant genotypes are at increased risk of PC. This was further confirmed by haplotype analysis, which showed that H2 comprising both GSTO1*A and GSTO2*G variant alleles represented a high-risk combination. However, the prognostic relevance of polymorphisms in GST omega genes was not found in our cohort of PC patients. Analysis of the role of other investigated GST polymorphisms (GSTM1, GSTT1, and GSTP1) in terms of PC prognosis has shown shorter survival in carriers of GSTP1*T/T (rs1138272) genotype than in those carrying at least one referent allele. In addition, the presence of GSTP1*T/T genotype independently predicted a four-fold higher risk of overall mortality among PC patients. This study demonstrated a significant prognostic role of GST polymorphism in PC.

scholarly journals Prostate Cancer Screening in Men with a Family History of Prostate Cancer: The Role of Partners in Influencing Men’s Screening Uptake

Urology ◽  
2007 ◽  
Vol 70 (4) ◽  
pp. 738-742 ◽  
Author(s):  
Bettina Meiser ◽  
Ruth Cowan ◽  
Anthony Costello ◽  
Graham G. Giles ◽  
Geoff J. Lindeman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Screening ◽  
Family History ◽  
Prostate Cancer Screening ◽  
Screening Uptake ◽  
History Of

scholarly journals ACE2: A key modulator of RAS and pregnancy

2021 ◽  
Author(s):  
Sonia Tamanna ◽  
Eugenie R. Lumbers ◽  
Saije K. Morosin ◽  
Sarah J. Delforce ◽  
Kirsty G. Pringle
Keyword(s):  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Current Knowledge ◽  
Severe Disease ◽  
Critical Role ◽  
Growth Restriction ◽  
Ang Ii ◽  
Renin Angiotensin ◽  
Increased Risk

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound protein containing 805-amino acids. ACE2 shows approximately 42% sequence similarity to somatic ACE but has different biochemical activities. The key role of ACE2 is to catalyse the vasoconstrictor peptide Angiotensin (Ang) II to Ang-(1-7), thus regulating the two major counterbalancing pathways of the renin-angiotensin system (RAS). In this way, ACE2 plays a protective role in end-organ damage by protecting tissues from the pro-inflammatory actions of Ang II. The circulating RAS is activated in normal pregnancy and is essential for maintaining fluid and electrolyte homeostasis and blood pressure. Renin-angiotensin systems are also found in the conceptus. In this review, we summarise the current knowledge on the regulation and function of circulating and uteroplacental ACE2 in uncomplicated and complicated pregnancies, including those affected by preeclampsia and fetal growth restriction. Since ACE2 is the receptor for SARS-CoV-2, and COVID-19 in pregnancy is associated with more severe disease and increased risk of abnormal pregnancy outcomes, we also discuss the role of ACE2 in mediating some of these adverse consequences. We propose that dysregulation of ACE2 plays a critical role in the development of preeclampsia, fetal growth restriction and COVID-19-associated pregnancy pathologies and suggest that human recombinant soluble ACE2 could be a novel therapeutic to treat and/or prevent these pregnancy complications.

The PROFILE feasibility study: Genetic prostate cancer risk stratification for targeted screening.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 22-22
Author(s):  
Christos Mikropoulos ◽  
Elena Castro ◽  
Elizabeth Bancroft ◽  
Elizabeth Page ◽  
Natalie Taylor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genetic Model ◽  
Cumulative Risk ◽  
Prostate Cancer Risk ◽  
Screening Tools ◽  
Risk Scores ◽  
Prostatic Biopsy ◽  
Increased Risk ◽  
Targeted Screening

22 Background: Prostate cancer (PC) screening is controversial and a better assessment of individualized PC risk is needed. Several single nucleotide polymorphisms (SNPs) conferring a cumulative risk of PC have been identified. We have explored the potential role of genetic markers for targeted screening in a population with increased risk of PC due to family history (FH). Methods: PROFILE was developed as a pilot study to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. We also evaluated the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools. One hundred sixteen men age 40 to 69 with FH of PC were enrolled between October 2009 and December 2012. Cumulative SNP risk scores were calculated by summing 59 risk alleles for each locus using the weighted effect (log-additive model). DW-MRI was performed in 50 patients. Participants were asked to undergo a 10 core PB regardless of baseline PSA. Results: Median age 53 (40 to 69) and median PSA was 1.15. One hundred and two men accepted to undergo a PB as primary PC screening. Twenty-three tumours were found (22.5% of biopsies) as well as seven men diagnosed with atypical small acinar proliferation (ASAP) (6.8%) and eight men with high-grade prostatic intraepithelial neoplasia (HG-PIN) (7.8%). In total 37.1% received an abnormal result. Out of the diagnosed PC 41% were intermediate or high risk and requiring treatment, which compares with 24% in general population screening. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed best in men with a normal PSA of <3(AUC 0.63). Analyses of a 78 SNP profile from the recent COGS results are underway. Conclusions: Ourresults indicate that PB is acceptable for PC screening in men with FH of PC. The significant AUC for DW-MRI would warrant a larger study. The incidence of ASAP is higher in this group than the general population.The SNP risk score was more predictive in men with PSA less than three where PB would not normally be undertaken, therefore an expanded study to investigate the role of genetic profiling in directing PB in PC screening is indicated.

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